Synaptic interactions within the thalamus are dynamically regulated in terms of their strength and efficacy. When this dynamic regulation fails to keep synaptic strength in the normal operating range, the thalamocortical circuitry enters a hypersynchronous state that leads to the development of generalized absence seizures. Inhibitory synapses mediated by the neurotransmitter gamma-aminobutyric acid (GABA) play a critical role in regulating synchrony, especially those synapses mediating reciprocal inhibition between thalamic reticular neurons. The long term goals of this project are to understand the pathways that lead to failure of the reciprocal inhbitory circuit and to design interventions that will prevent seizures. In this proposal we will address three major questions relevant to the efficacy of these inhibitory synapses: 1) What are the roles of glial GABA uptake via the transporter GAT-3 and glutamine-dependent GABA cycling in the context of epileptic network oscillations? 2) What is the extent and potency of specific inhibitory connections within the thalamic reticular nucleus? and 3) Can the reciprocal inhibition between thalamic reticular cells be functionally overcome by excitatory corticothalamic and/or thalamocortical synaptic responses? Overall these three questions will address the central theme - synaptic and perisynaptic factors that critically regulate excitability in the reticular nucleus. Our approach will be a combination of whole-cell voltage and current clamp recordings of thalamic neurons in acute rat brain slices, combined with laser scanning 3hotolytic glutamate uncaging, dynamic clamp, genetically-modified mice, and pharmacological manipulation 3f the GABA neuron-glial transport system. The results of these experiments will provide insight regarding therapeutic approaches that are likely to be effective in the treatment of generalized absence seizures.